Abstract Many human pathogenic viruses exploit the host-cell proteases of the proprotein convertase (PC) family for their own benefit. The proteolytic processing of viral surface proteins is a mechanism by which viruses regulate their infectivity. The crucial role of the proteolytic regulation of viral maturation and replication makes PCs a feasible target for antiviral intervention. We have found that the highly oncogenic HPV types, HPV16 and HPV18, differ in their PC selectivity along the same line that divides the two PC reaction specificity groups composed of furin and PC5/PACE4/PC7. It is hypothesized that the interplay of HPV-type PC reactivity and the PC gene expression profile of keratinocytes at anatomical sites of HPV infection may determine known HPV-type differences in cell tropism and infectivity. Our long term goals are to gain insight into the details of this widespread mechanism of virus replication control system and strengthen the notion that PC inhibition is a viable antiviral strategy. In order to test this hypothesis, it will be investigated first, the differences in PC reactivity and selectivity of high-risk and low-risk HPV types, including the characterization of three potential PC cleavage sites. And second, the dependence of HPV-type infectivity on the PC genes expression of keratinocytes at various anatomical sites of HPV infection.